Multi-drug titration and evaluation

Abstract

Titration of a combination of drugs or treatment modalities within individual subjects is carried out using an evolutionary operation (EVOP) direct-search procedure such as the Nelder-Mead simplex. Desirability functions are incorporated to define the main response of interest and additional responses or constraints. Statistical methodology for determining whether the titrated treatment combination has resulted in an improvement in patient response and for evaluating whether a therapeutic synergism exists is also incorporated. Inferences can be made about the efficacy of the combination or about the individual drugs or treatment modalities that comprise the combination. This approach allows every patient the potential to benefit from the combination under study and permits the consideration of multiple endpoints simultaneously.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The invention generally relates to the titration of multi-modality therapy regimens. In particular, the invention provides methods of titrating and evaluating multi-modalitiy therapy regimens using an evolutionary operation (EVOP) approach.[0003]2. Background of the Invention[0004]The use of multiple medications and / or treatment modalities in the treatment of individual patients is an increasingly commonplace occurrence. The elderly population, who consume the most drugs and in whom relative drug consumption continues to increase, is rapidly growing in the United States and other developed nations. The pace of new drug development, from drug discovery to drug production, has accelerated greatly, and single diseases are now treated with multiple drugs targeting different biochemical pathways or different aspects in the pathophysiology of a disease. This increase in drug consumption brings with it a dramatic increase in t...

AI Technical Summary

Benefits of technology

[0015]In a preferred embodiment of the present invention, the evolutionary operational direct search algorithm that is applied is the Nelder-Mead algorithm. However, other direct search algorithms may also be utilized, for example, direct search algorithms based on the construction of complexes rather than simplexes. (See, for example, Box, 1965 and Box, 1969). The advantage of utilizing direct search algorithms is that the use of derivatives is not required, so that no assumptions need be made regarding the underlying relationships between the modalities which are administered and the endpoints being observed.

Problems solved by technology

This increase in drug consumption brings with it a dramatic increase in the potential for drug interactions and adverse drug reactions.

The difficulty arrives in attempting to translate this approach to determining dosages in the case where multiple drugs and / or other treatment modalities are being prescribed in the treatment of a single disease, or where the consideration of multiple endpoints is needed in the case where a single treatment is prescribed.

There is currently no systematic or efficient method for determining dosages in multi-drug regimens.

Unfortunately, this approach does not account for potential interactions among the drugs, which may be crucial when searching for the most desirable therapy.

Not only is combination dosing difficult for practicing physicians in the day-to-day care of their patients, but it also presents a problem in both clinical trials research and drug evaluation research.

There are several problems with this approach.

The first problem is that if no difference in response is found between the groups, this does not necessarily mean that the new combination is ineffective.

The lack of effect may lie in the dose chosen for use in the study.

Secondly, this approach does not provide any information regarding the location of more effective doses if the combination is not found to differ from the standard.

On the other hand, if the new combination is found to be more effective, approximately half the subjects enrolled in the study, those randomized to the standard treatment, have not benefitted from the trial.

Finally, even with early stopping rules, the time a patient spends on the inferior treatment can have lasting detrimental effects.

These problems can lead to difficulties with patient recruitment and adherence to the study protocol.

While this is a somewhat effective approach, it is limited in its application for several reasons.

Firstly, this approach requires the use of predetermined, fixed combinations, none of which may actually correspond to the best treatment.

Furthermore, these studies quickly become expensive due to the numerous dose combinations required.

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